Podocytes are highly differentiated ceils that are important for glomerular homeostasis. Podocytes are injured in many glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, and diabetes mellitus. From the standpoint of progressive glomerular disease, it is important to recognize that if the early structural changes are not reversed, severe and progressive glomerular damage develops. The TGF-beta pathway is one of several classical signaJ transduction pathways that control cell fate. Our studies in TGF-beta transgenic mice realeaved a strong correlation between podocyte loss and progression of glomerular diseases. Here we developed a unique comprehensive signaling approach that integrates structural and classical signaling pathways. We will explore at the molecular level how the altered dynamics of the actin cytoskeleton in synaptopodin deficient mice modulate a major signaling pathway, i.e. the TGF-beta signaling pathway in podocytes, thereby increasing the severity and mortality of TGF-beta induced glomerulosclerosis. We will test the hypothesis that synaptopodin is a downstream cytoskeletal target of TGFbeta and that synaptopodin represents a disease modifier and modulates the severity or progression of glomerular disease by altering the response of the podocyte actin cytoskeleton to TGF-beta. if our hypothesis is correct, the work proposed here should have broad significance in the long-term, since it may provide the rationale for new areas of investigation: a) revealing molecular signaling pathways in podocyte at the interface of structural and classical signaling pathways; b) development of novel therapies that tackle proteinuria and progression of glomerular diseases.